Adolescent idiopathic scoliosis (AIS) is the most common type of scoliosis. Controlling its curve progression is the most important clinical task. Although recent genome-wide association studies (GWASs) identified several susceptibility loci associated with the development of AIS, the etiology of curve progression has been still unknown. Our previous GWAS has identified that rs12946942 showed significant association with severe AIS. To confirm the association, we conducted an international meta-analysis using four cohorts with different ethnicity. We analyzed 2272 severe AIS cases and 13,859 controls in total, and found the replication of significant association of rs12946942 (combined P = 7.23×10−13; odds ratio = 1.36, 95% confidence interval = 1.25−1.49). In silico analyses suggested that SOX9 is the most likely susceptibility gene for AIS curve progression in the locus.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Members of the Japan Scoliosis Clinical Research Group (JSCRG) are listed below Acknowledgements.
Weinstein SL. Natural history. Spine (Phila Pa 1976). 1999;24:2592–600.
Ueno M, Takaso M, Nakazawa T, Imura T, Saito W, Shintani R, et al. A 5-year epidemiological study on the prevalence rate of idiopathic scoliosis in Tokyo: school screening of more than 250,000 children. J Orthop Sci. 2011;16:1–6.
Ward K, Ogilvie J, Argyle V, Nelson L, Meade M, Braun J, et al. Polygenic inheritance of adolescent idiopathic scoliosis: a study of extended families in Utah. Am J Med Genet A. 2010;152A:1178–88.
Wynne-Davies R. Genetic aspects of idiopathic scoliosis. Dev Med Child Neurol. 1973;15:809–11.
Takahashi Y, Kou I, Takahashi A, Johnson TA, Kono K, Kawakami N, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet. 2011;43:1237–40.
Ogura Y, Kou I, Miura S, Takahashi A, Xu L, Takeda K, et al. A functional SNP in BNC2 is associated with adolescent idiopathic scoliosis. Am J Hum Genet. 2015;97:337–42.
Sharma S, Londono D, Eckalbar WL, Gao X, Zhang D, Mauldin K, et al. A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. Nat Commun. 2015;6:6452.
Zhu Z, Tang NL, Xu L, Qin X, Mao S, Song Y, et al. Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls. Nat Commun. 2015;6:8355.
Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet. 2013;45:676–9.
Ryzhkov II, Borzilov EE, Churnosov MI, Ataman AV, Dedkov AA, Polonikov AV. Transforming growth factor beta 1 is a novel susceptibility gene for adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2013;38:E699–704.
Qiu Y, Mao SH, Qian BP, Jiang J, Qiu XS, Zhao Q, et al. A promoter polymorphism of neurotrophin 3 gene is associated with curve severity and bracing effectiveness in adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2012;37:127–33.
Peng Y, Liang G, Pei Y, Ye W, Liang A, Su P. Genomic polymorphisms of G-protein estrogen receptor 1 are associated with severity of adolescent idiopathic scoliosis. Int Orthop. 2012;36:671–7.
Jiang J, Qian B, Mao S, Zhao Q, Qiu X, Liu Z, et al. A promoter polymorphism of tissue inhibitor of metalloproteinase-2 gene is associated with severity of thoracic adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2012;37:41–7.
Wu J, Qiu Y, Zhang L, Sun Q, Qiu X, He Y. Association of estrogen receptor gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2006;31:1131–6.
Zhang HQ, Lu SJ, Tang MX, Chen LQ, Liu SH, Guo CF, et al. Association of estrogen receptor beta gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2009;34:760–4.
Chen Z, Tang NL, Cao X, Qiao D, Yi L, Cheng JC, et al. Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population. Eur J Hum Genet. 2009;17:525–32.
Yeung HY, Tang NL, Lee KM, Ng BK, Hung VW, Kwok R, et al. Genetic association study of insulin-like growth factor-I (IGF-I) gene with curve severity and osteopenia in adolescent idiopathic scoliosis. Stud Health Technol Inform. 2006;123:18–24.
Takahashi Y, Matsumoto M, Karasugi T, Watanabe K, Chiba K, Kawakami N, et al. Replication study of the association between adolescent idiopathic scoliosis and two estrogen receptor genes. J Orthop Res. 2011;29:834–7.
Ogura Y, Takahashi Y, Kou I, Nakajima M, Kono K, Kawakami N, et al. A replication study for association of 53 single nucleotide polymorphisms in a scoliosis prognostic test with progression of adolescent idiopathic scoliosis in Japanese. Spine (Phila Pa 1976). 2013;38:1375–9.
Ogura Y, Takahashi Y, Kou I, Nakajima M, Kono K, Kawakami N, et al. A replication study for association of 5 single nucleotide polymorphisms with curve progression of adolescent idiopathic scoliosis in Japanese patients. Spine (Phila Pa 1976). 2013;38:571–5.
Miyake A, Kou I, Takahashi Y, Johnson TA, Ogura Y, Dai J, et al. Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PLoS ONE. 2013;8:e72802.
Fan YH, Song YQ, Chan D, Takahashi Y, Ikegawa S, Matsumoto M, et al. SNP rs11190870 near LBX1 is associated with adolescent idiopathic scoliosis in southern Chinese. J Hum Genet. 2012;57:244–6.
Song YQ, Karasugi T, Cheung KM, Chiba K, Ho DW, Miyake A, et al. Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant. J Clin Invest. 2013;123:4909–17.
Grauers A, Wang J, Einarsdottir E, Simony A, Danielsson A, Akesson K, et al. Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis. Spine J. 2015;15:2239–46.
Grauers A, Danielsson A, Karlsson M, Ohlin A, Gerdhem P. Family history and its association to curve size and treatment in 1,463 patients with idiopathic scoliosis. Eur Spine J. 2013;22:2421–6.
Andersen MO, Christensen SB, Thomsen K. Outcome at 10 years after treatment for adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2006;31:350–4.
Grauers A, Topalis C, Moller H, Normelli H, Karlsson MK, Danielsson A, et al. Prevalence of back problems in 1069 adults with idiopathic scoliosis and 158 adults without scoliosis. Spine (Phila Pa 1976). 2014;39:886–92.
Gerdhem P, Akesson K. Rates of fracture in participants and non-participants in the Osteoporosis Prospective Risk Assessment study. J Bone Jt Surg Br. 2007;89:1627–31.
McGuigan FE, Larzenius E, Callreus M, Gerdhem P, Luthman H, Akesson K. Variation in the BMP2 gene: bone mineral density and ultrasound in young adult and elderly women. Calcif Tissue Int. 2007;81:254–62.
Dixon JR, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget JE, Lee AY, et al. Chromatin architecture reorganization during stem cell differentiation. Nature. 2015;518:331–6.
Consortium GT. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60.
Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. 1999;22:85–9.
Akiyama H. Control of chondrogenesis by the transcription factor Sox9. Mod Rheumatol. 2008;18:213–9.
Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanovic M, et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994;372:525–30.
Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron. 2002;34:933–44.
Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr., Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002;71:663–8.
Zhang X, Cowper-Sal lari R, Bailey SD, Moore JH, Lupien M. Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus. Genome Res. 2012;22:1437–46.
We are grateful to the individuals who participated in this study. We thank all participating subjects and clinical staff at collaborating institutes. We specially thank Y. Takahashi, T. Oguma and the members of Laboratory for Genotyping Development for technical assistance. This work was supported by Japan Agency for Medical Research and Development (AMED) (contract no. 18ek0109212h0002 to SI), Japan Orthopaedics and Traumatology Foundation (to KT and NO), Hong Kong Health and Medical Research Fund (HMRF No. 04152256) (to Y-QS) and the Swedish Research Council (No. K-2013-52X-22198-01-3) (to AG and PG).
Japan Scoliosis Clinical Research Group (JSCRG):
Noriaki Kawakami12, Taichi Tsuji12, Koki Uno13, Teppei Suzuki13, Manabu Ito14, Shohei Minami15, Toshiaki Kotani15, Tsuyoshi Sakuma15, Haruhisa Yanagida16, Hiroshi Taneichi17, Ikuho Yonezawa18, Hideki Sudo19, Kazuhiro Chiba20, Naobumi Hosogane21, Kotaro Nishida22, Kenichiro Kakutani22, Tsutomu Akazawa23, Takashi Kaito24, Kei Watanabe25, Katsumi Harimaya26, Yuki Taniguchi27, Hideki Shigematsu28, Satoru Demura29, Takahiro Iida30, Katsuki Kono31, Eijiro Okada2, Nobuyuki Fujita2 and Mitsuru Yagi2